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Altered Gut Microbiome under Antiretroviral Therapy: Impact of Efavirenz and Zidovudine.

ABSTRACT: Millions of individuals currently living with HIV globally are receiving antiretroviral therapy (ART) that suppresses viral replication and improves host immune responses. The involvement of gut microbiome during HIV infection has been studied, exposing correlation with immune status and inflammation. However, the direct effect of ART on gut commensals of HIV-infected individuals has been mostly overlooked in microbiome studies. We used 16S rRNA sequencing (Illumina MiSeq) for determining the microbiota composition of stool samples from 16 viremic patients before and one year after ART. We also tested the direct effect of 15 antiretrovirals against four gut microbes, namely, Escherichia coli, Enterococcus faecalis, Bacteroides, and Prevotella to assess their in vitro antibacterial effect. 16S rRNA analysis of fecal samples showed that effective ART for one year does not restore the microbiome diversity in HIV-infected patients. A significant reduction in α-diversity was observed in patients under non-nucleoside reverse transcriptase inhibitors; (NNRTI; 2 NRTI+NNRTI; NRTIs are nucleoside reverse transcriptase inhibitors) as compared to ritonavir-boosted protease inhibitors (PI/r; 2 NRTI+PI/r). Prevotella (P = 0.00001) showed a significantly decreased abundance in patients after ART (n = 16). We also found the direct effect of antivirals on gut microbes, where zidovudine (ZDV) and efavirenz (EFV) showed in vitro antimicrobial activity against Bacteroides fragilis and Prevotella. EFV also inhibited the growth of E. faecalis. Therefore, we observed that ART does not reverse the HIV-induced gut microbiome dysbiosis and might aggravate those microbiota alterations due to the antibacterial effect of certain antiretrovirals (like EFV, ZDV). Our results imply that restructuring the microbiota could be a potential therapeutic target in HIV-1 patients under ART.

SUBMITTER: Ray S

PROVIDER: S-EPMC8154435 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCombination antiretroviral therapy (cART) use in pregnancy has been associated with hormonal dysregulation. We performed a secondary retrospective analysis of longitudinal progesterone and estradiol levels in pregnancy using specimens from the Protease Inhibitors to Reduce Malaria Morbidity in HIV-infected Pregnant Women study, which randomized Ugandan human immunodeficiency virus (HIV)-infected ART-naive women to initiate either lopinavir/ritonavir (LPV/r)-based or efavirenz (EFV)-based cART.MethodsThree hundred twenty-six women (160 randomized to the EFV arm and 166 women to the LPV/r arm) with at least 1 plasma sample collected during pregnancy were included. Enrollment samples collected prior to cART initiation were used as a cART-naive comparator group. Hormone levels were quantified by enzyme-linked immunosorbent assay.ResultsEstradiol levels were differentially affected by the 2 cART regimens. Exposure to LPV/r was associated with an increase in estradiol (P < .0001), whereas exposure to EFV was associated with a decrease in estradiol (P < .0001), relative to the cART-naive gestationally matched comparator group. Lower estradiol levels correlated with small for gestational age (SGA) (P = .0019) and low birth weight (P = .019) in the EFV arm, while higher estradiol levels correlated with SGA in the LPV/r arm (P = .027). Although progesterone levels were similar between treatment arms, we observed an association between SGA and lower progesterone in the LPV/r arm (P = .04). No association was observed between hormone levels and preterm birth in either arm. Levels of progesterone and estradiol were lower in cases of stillbirth, and levels of both hormones declined immediately prior to stillbirth in 5 of 8 cases.ConclusionsCombination ART regimens differentially affect estradiol levels in pregnancy, a hormone critical to the maintenance of a healthy pregnancy. Identifying cART regimens that minimize perinatal HIV transmission without contributing to hormonal dysregulation represents an urgent public health priority.Clinical trials registrationNCT00993031.

Project description:This study characterized compositional and functional shifts in the intestinal and oral microbiome in HIV-positive patients on antiretroviral therapy compared to HIV-negative individuals. Seventy-nine specimens were collected from 5 HIV-positive and 12 control subjects from five locations (colon brush, colon wash, terminal ileum [TI] brush, TI wash, and saliva) during colonoscopy and at patient visits. Microbiome composition was characterized using 16S rRNA sequencing, and microbiome function was predicted using bioinformatics tools (PICRUSt and BugBase). Our analysis indicated that the β-diversity of all intestinal samples (colon brush, colon wash, TI brush, and TI wash) from patients with HIV was significantly different from patients without HIV. Specifically, bacteria from genera Prevotella, Fusobacterium, and Megasphaera were more abundant in samples from HIV-positive patients. On the other hand, bacteria from genera Ruminococcus, Blautia, and Clostridium were more abundant in samples from HIV-negative patients. Additionally, HIV-positive patients had higher abundances of biofilm-forming and pathogenic bacteria. Furthermore, pathways related to translation and nucleotide metabolism were elevated in HIV-positive patients, whereas pathways related to lipid and carbohydrate metabolism were positively correlated with samples from HIV-negative patients. Our analyses further showed variations in microbiome composition in HIV-positive and negative patients by sampling site. Samples from colon wash, colon brush, and TI wash were significant between groups, while samples from TI brush and saliva were not significant. Taken together, here, we report altered intestinal microbiome composition and predicted function in patients with HIV compared to uninfected patients, though we found no changes in the oral microbiome. IMPORTANCE Over 37 million people worldwide are living with HIV. Although the availability of antiretroviral therapy has significantly reduced the number of AIDS-related deaths, individuals living with HIV are at increased risk for opportunistic infections. We now know that HIV interacts with the trillions of bacteria, fungi, and viruses in the human body termed the microbiome. Only a limited number of previous studies have compared variations in the oral and gastrointestinal microbiome with HIV infection. Here, we detail how the oral and gastrointestinal microbiome changes with HIV infection, having used 5 different sampling sites to gain a more comprehensive view of these changes by location. Our results show site-specific changes in the intestinal microbiome associated with HIV infection. Additionally, we show that while there were significant changes in the intestinal microbiome, there were no significant changes in the oral microbiome.

Project description:Chronic inflammation is a hallmark of human immunodeficiency virus (HIV) infection and a risk factor for the development and progression of age-related comorbidities. Although HIV-associated gut dysbiosis has been suggested to be involved in sustained chronic inflammation, there remains a limited understanding of the association between gut dysbiosis and chronic inflammation during HIV infection. Here, we investigated compositional changes in the gut microbiome and its role in chronic inflammation in patients infected with HIV. We observed that the gut microbiomes of patients with low CD4 counts had reduced alpha diversity compared to those in uninfected controls. Following CD4 recovery, alpha diversity was restored, but intergroup dissimilarity of bacterial composition remained unchanged between patients and uninfected controls. Patients with HIV had higher abundance of the classes Negativicutes, Bacilli, and Coriobacteriia, as well as depletion of the class Clostridia. These relative abundances positively correlated with inflammatory cytokines and negatively correlated with anti-inflammatory cytokines. We found that gut dysbiosis accompanying HIV infection was characterized by a depletion of obligate anaerobic Clostridia and enrichment of facultative anaerobic bacteria, reflecting increased intestinal oxygen levels and intestinal permeability. Furthermore, it is likely that HIV-associated dysbiosis shifts the immunological balance toward inflammatory Th1 responses and encourages proinflammatory cytokine production. Our results suggest that gut dysbiosis contributes to sustaining chronic inflammation in patients with HIV infection despite effective antiretroviral therapy and that correcting gut dysbiosis will be effective in improving long-term outcomes in patients. IMPORTANCE Chronic inflammation is a hallmark of HIV infection and is associated with the development and progression of age-related comorbidities. Although the gastrointestinal tract is a major site of HIV replication and CD4+ T-cell depletion, the role of HIV-associated imbalance of gut microbiome in chronic inflammation is unclear. Here, we aimed to understand the causal relationship between abnormalities in the gut microbiome and chronic inflammation in patients with HIV. Our results suggest HIV-associated gut dysbiosis presents a more aerobic environment than that of healthy individuals, despite prolonged viral suppression. This dysbiosis likely results from a sustained increase in intestinal permeability, which supports sustained bacterial translocation in HIV patients, despite effective therapy. Additionally, we observed that several bacterial taxa enriched in HIV patients were associated with increased expression of inflammatory cytokines. Collectively, these results suggest that gut dysbiosis plays an important role in chronic inflammation in HIV patients.

Project description:ObjectiveThe study objective was to compare the microbial composition of patients with dermatomyositis (DM) and healthy controls (HCs) and determine whether microbial alterations are associated with clinical manifestations of DM.MethodsThe 16S ribosomal RNA gene sequencing was performed on fecal samples from patients with DM and HCs. Microbial composition and diversity were compared between subjects with DM and HCs and in association with several DM-specific clinical variables, including myositis-specific autoantibodies (MSAs). Differentially abundant microbial taxa and genes associated with clinical characteristics were identified, and functional analysis was performed using predicted metagenomics. Dietary intake was assessed using a 24-hour dietary recall.ResultsThe fecal microbiome of 36 patients with DM and 26 HCs were analyzed. Patients with DM trended toward lower microbial diversity compared with HCs. The higher physician global damage score was significantly correlated with the lower microbial diversity in patients with DM. Patients with interstitial lung disease (ILD)-associated MSA (antisynthetase antibody (ab), anti-melanoma differentiation-associated protein 5 ab, n = 12) had significant differences in microbial composition and lower microbial diversity compared with HCs. Differential abundance testing demonstrated a unique taxonomic signature in the ILD-MSA subgroup, and predictive metagenomics identified functional alterations in a number of metabolic pathways. A significant increase in the relative abundance of Proteobacteria was positively correlated with multiple pathways involved in lipopolysaccharide synthesis and transport in the ILD-MSA group.ConclusionPatients with DM, particularly with ILD-associated MSAs, have lower microbial diversity and a distinct taxonomic composition compared with HCs. Further studies are needed to validate our findings and elucidate specific pathogenetic mechanisms that link the gut microbiome to clinical and pathological features of DM.

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Altered Gut Microbiome under Antiretroviral Therapy: Impact of Efavirenz and Zidovudine.

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